Lometrexol is the generic name given to 5,10-dideazatetrahydrofolic acid, also referred to as DDATHF. Lometrexol is a member of a new class of antitumor agents which have been found to specifically inhibit glycinamide ribonucleotide (GAR) transformylase, an enzyme required in the initial stages of purine biosynthesis, see J. Med. Chem., 28, 914 (1985). Several of these GAR-transformylase inhibitors are described, along with their antitumor utilities, by Taylor et al. in U.S. Pat. Nos. 4,684,653, 4,833,145, 4,902,796, 4,871,743 and 4,882,334. GAR-transformylase inhibitors are also known to be useful in treating conditions such as gout, psoriasis, mycosis fungoides, autoimmune disorders, rheumatoid arthritis and other inflammatory disorders, and during organ transplantation and other related immunosuppressant related conditions.
Lometrexol has been studied clinically and shown to be a potent antitumor agent, especially against solid tumors such as colorectal, lung, breast, head and neck and pancreatic; Young et al., Proc. Amer. Assoc. Cancer Research, 31, 1053 (1990). Like most other antitumor agents, Lometrexol exhibits some undesirable side effects, in addition to its efficacy against tumors; Muggia et al., Proc. Amer. Soc. Clinical Oncology, 9, 1285 (1990). Typical side effects observed to date include anorexia, weight loss, mucositis, leukopenia, anemia, hypoactivity and dehydration.
We have now discovered that the toxic effects of lometrexol and related GAR-transformylase inhibitors and other antifolate agents which bind to folate binding protein (FBP) (see, e.g., Kane, et al., Laboratory Investigation, 60, 737 (1989)) can be significantly reduced by the presence of a FBP binding agent, without adversely affecting therapeutic efficacy. The present invention thus provides a method for improving the therapeutic utility of GAR-transformylase inhibitors and other antifolates by co-administering a FBP binding agent to the host under going treatment.